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Chapter 6

SYNTHESIS OF 1, 4
-DIHYROPYRIDINE
DERIVATIVES
INTRODUCTION
Dihydropyridine chemistry began in 1882 when Arthur Hantzsch (1) published the
synthesis which now bears his name. In the subsequent 50 years modifications
of the original synthesis were developed and some reactions of dihydropyridines
were studied. Dihydropyridines also play a role as intermediates in the reactions
of pyridines, e.g., in nucleophilic substitutions and reductions as well as
acylation in the presence of pyridine. Hantzsch assumed the product from the
reaction of ethyl aceto-acetate, acetaldehyde and ammonia now known to be a
2,3-dihydropyridine, but it was soon recognized to be the 1,4 isomer. However,
rigorous proof was presented only much later.
Number of 1,4-dihydropyridine derivatives have been synthesized by three
component condensation using aldehyde, ethyl aceto acetate and ammonium
acetate

(2)

also catalyst free and solvent free synthesis have been found using

aldehydes, amines, diethyl acetylene dicarboxylate and malononitrile /ethyl


cyanoacetate

.Bayer

(3)

and knovengel

(4)

Hantzsch reaction.

203

(5)

also gave some modification in

Recently synthesis of 1,4-dihydropyridine derivatives has been described using


as a catalyst clay K-10 (6), Bismuth nitrate (7), Barium nitrate.
Some 1,4 dihyropyridine derivatives were also synthesized by catalyst free and
use of environmental being solvent as water in multi-component synthesis. it is
an efficient and simple un-catalyzed synthesis of 1,4-dihydropyridine
derivatives in an aqueous media via one pot three component reaction of
aldehydes, dicarbonyl compound and liq. ammonia as a source of nitrogen at
50-60oC using green solvent (8).

CHO

R
O

O
O

+ 2
R

+
R1 Liq.NH3

H2 O
50-60 C R

R
1

3
Me

R1= OEt or OMe

Cozzy

and coworkers

have

(9)

Me

synthesized

series

of

4-phenyl-1,4-

dihydropyridines bearing imidazol-1-yl or pyridine-3-yl moieties on the phenyl


ring, with the aim of combining Ca 2+ antagonism and thermb-oxane A2(TxA2)
synthase inhibition in the same molecules. Some of the compounds showed
significant combined activity in vitro, while other showed single activity.

204

E. Angeles1, H. Santilln and coworkers

through Hantzsch reaction of 5-

(10)

hydroxy-2-nitrobenzaldehyde gave the expected 1,4- and 1,2 dihydropyridines.


However, the same reaction with 2-nitrobenzaldehyde gave four compound.

METHOD OF PREPARATION
The synthesis of 1, 4 dihyropyridine derivatives was synthesized by a single
step reaction called as Hantzsch reaction. It is one step process.

1) Synthesis of 3, 5 diethyl- 2, 6 dimethyl 4-(pdi-amino methyl phenyl) 1,4-dihyropyridine-3,5


dicarboxylate.
For the preparation

of 3,5 diethyl 2,6 dimethyl 4(p-diamino methyl phenyl )

1,4 dihyropyridine 3,5 dicarboxylate we take 7.45 gm of diamino-benzaldehyde


(1 mole) , 63.22 ml of ethyl aceto-acetate (2 mole) and conc. ammonium
hydroxide 9.6 ml with 60 ml ethanol in a round bottom flask, fitted with a reflux
condenser. All the weights were calculated through their molecular weight. All
the above mixture was heated around 10hrs on a water bath. The reaction
mixture was cooled and the product was precipitate from the reaction mixture
with continuous addition of cold water. Allow the solution stand for sometime
after that the precipitate was filtered off and wash with 60% ethyl alcohol .when
a solid is completely crystallized and dried out, it was recrystallized with ethyl
alcohol.
The compound was named as 1, 4 dihyropyridine [A-1]
205

REACTION SCHEME-1
Me
C2H5O2C

Me

CO2C2H5

CH2
+

C
CH3

H3C

O
CHO
NH4OH in ethanol
heated for 10hrs.
Me

Me
N

C2H5O

H3 C

OC2H5

CH3

2) Preparation of 3,5-diethyl-2,6-dimethyl-4-(2hyroxy-phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
For

the

synthesis

of

3,5-diethyl-2,6-dimethyl-4-(2-hyroxyphenyl)-1,4

dihyropyridine-3,5-dicarboxylate10.5ml solution of 2-hydroxy-benzaldehyde,


25.29ml of ethyl aceto-acetate and 3.8 ml of conc.ammonium hydroxide with
24ml ethanol were taken in a round bottom flask ,fitted with reflux condenser.
The reaction mixture was heated for 8hours on water bath. when the precipitate
were appear in the bottom of the flask reaction mixture were stand for cool
down. After that the mixtures was taken in another flask and carefully add cold
water. The precipitate was filtered off and
206

washed with 60% of aqueous

ethanol .when the solid product crystallized out; it was dried and recrystallized
with ethyl alcohol to remove for all impurities.
The 1,4- dihyropyridine named as [A2].

REACTION SCHEME-2
C 2H 5O 2 C

CO2C2H5
C
+

C
H3 C

CH2
+

OH

CH3
O

CHO

NH4OH in ethanol
heated for 8hrs.

OH

C2H5O

H3 C

OC2H5

CH3

3) Preparation of 3,5-diethyl-2,6-dimethyl-4-(pchloro-phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
For

the

synthesis

of

3,5-diethyl-2,6-dimethyl-4-(p-chlorophenyl)

1,4

dihyropyridine-3,5-dicarboxylate weigh 12.2gm of p-chloro-benzaldehyde,


25.29ml of ethyl aceto-acetate and 3.8 ml of conc.ammonium hydroxide with
24ml ethanol were taken in a round bottom flask ,fitted with reflux condenser.
207

The reaction mixture was heated for 10hours on water bath .when the
precipitate were appear in the bottom of the flask reaction mixture were stand
for cool down. After that the mixtures was taken in another flask and carefully
add cold water. The precipitate was filtered off and

washed with 60% of

aqueous ethanol .when the solid product crystallized out; it was dried and
recrystallized with ethyl alcohol to remove for all impurities.
The 1,4- dihyropyridine named as [A3].

REACTION SCHEME-3:
Cl

C2H5O2C

CO2C2H5

C
C

CH2

H3C

CH3
O

CHO

NH4OH in ethanol
heated for 10hrs.
Cl

C2H5O

H3C

CH3

208

OC2H5

4) Preparation

of

3, 5-diethyl-2, 6-dimethyl- 4-

(p-methoxy phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
A mixture of p-methoxy-benzaldehyde 12.1ml, ethyl aceto-acetate 25ml and
conc.ammonium hydroxide 3.8ml was taken in round bottom flask containing
25ml ethanol. Round bottom flask was fitted with a condenser the mixture was
heated for 5hours on water bath. The reaction was cooled the solid product was
filtered and washed with 60% aqueous ethanol. When the solid product was
completely dried out; recrystallized with ethyl alcohol. The 1,4 dihyropyridine
named as [A4]

REACTION SCHEME-4

209

OCH3

C2H5O2C

CO2C2H5
C

CH2
+

C
CH3

H3C

O
CHO

NH4OH in ethanol
heated for 5hrs.
OCH3

C2H5O

H3 C

CH3

210

OC2H5

References

1. Arthur, Hantzsch. 1882.


2. A revisit to the hantzsch reaction: unexpected products beyond 1,4dihyropyridines . Shen Li, Cao Song et. al. 2009, Green Chemistry, Vol. 11, pp.
1414-1420.
3. A grinding -induced catalyst and solvent free synthesis of highly
functionalized 1,4-dihyropyridine via a domino multicomponent reaction.
Siddharth, Kumar Atul and Sharma. 2011, Green Chemistry, Vol. 13, pp.
2017-2020.
4. Bayer, C.
5. Knovengel.
6. Synthesis of 1,4-dihyropyridine derivatives under aqueous media. Nahid,
Zonouz Moshtaghi Adeleh and Sahranavard. S1, 2010, Journal of Chemistry,
Vol. 7, pp. S372-S376.
7. A microwave -assisted bismuth nitrate -catalyzed unique route toward 1,4dihyropyridines. al., Bandyopadhyay Debasish et. 2012, Molecules, Vol. 17,
pp. 2643-2662.

211

8. An efficient and simple un-catalysed synthesis of 1,4-dihyropyridines in an


aqueous media . Sandeep, Makone S. Sangita and Niwadange N. 5, 2012, Der
Chemica Sinica, Vol. 3, pp. 1293-1296.
9. Imidazol-1-yl and pyridin-3-yl derivatives of 4-phenyl-1,4-dihyropyridine
combining ca2+ antagonism and thromboxane A2 synthase inhibition. al.,
P.Cozzi and C.German et. 1993, Journal of Medicinal Chemistry, Vol. 36, pp.
2964-2972.
10. Rearrangment of o-nitrobenzaldehyde in the hantzsch reaction. al., Angeles
E. et. 2001, Journal of Molecules, Vol. 6, pp. 683-693.
11. Synthesis and QSAR studies of 4-substituted phenyl -2,6-dimethyl -3,5-bisN-(substituted phenyl)carbamoyl-1,4-dihyropyridine as potential antituberculer
agents. al., Desai Bhavik et. 2001, Bioorganic & Medicinal Chemistry , Vol. 9,
pp. 1993-1998.

212

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